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101.
Mirjana Urosevic Patrick A Oberholzer Tanja Maier Jürg Hafner Elisabeth Laine Herbert Slade Bernd Benninghoff Günter Burg Reinhard Dummer 《Clinical cancer research》2004,10(15):4959-4970
PURPOSE: Imiquimod represents a synthetic local immune response modifier that has demonstrated efficacy in clearing basal cell carcinoma. Via interaction with Toll-like receptor 7 on immune cells, imiquimod induces local production of cytokines, such as interferon (IFN)-alpha. EXPERIMENTAL DESIGN: To more closely define and elucidate mechanisms leading to basal cell carcinoma clearance in vivo, we examined gene expression profiles of skin basal cell carcinoma before and after treatment with 5% imiquimod cream (Aldara) by using high-density oligonucleotide arrays. RESULTS: We show that imiquimod predominantly induces genes involved in different aspects of immune response. In addition to effects on immunity, imiquimod treatment modulates the expression of genes involved in the control of apoptosis and oncogenesis. Array data indicated that imiquimod treatment induces expression of opioid growth factor receptor, a molecule recently reported to be a target for antitumor antibody responses. Immunohistochemistry revealed in vivo up-regulation of opioid growth factor receptor protein on tumor and on infiltrating cells after treatment. By using basal cell carcinoma cell lines treated with IFN-alpha or imiquimod, we show that opioid growth factor receptor up-regulation is IFN-alpha-mediated, rather then directly imiquimod-mediated. By using tissue microarray containing 52 basal cell carcinomas, we demonstrate opioid growth factor receptor expression in almost half of the cases. Expression of opioid growth factor receptor correlated with a longer recurrence-free period in basal cell carcinoma that recurred after radiotherapy (Kaplan-Meier analysis, P = 0.041). CONCLUSIONS: In addition to its immunomodulatory and antiproliferative activity, opioid growth factor receptor seems to have a prognostic significance in basal cell carcinoma patients. Our data add to the growing list of basal cell carcinoma-associated tumor antigens. 相似文献
102.
Circulating growth factor levels are associated with tumorigenesis in neurofibromatosis type 1. 总被引:2,自引:0,他引:2
George A Mashour Pablo Hernáiz Driever Melanie Hartmann Stephanie N Drissel Tingguo Zhang Bianca Scharf Ursula Felderhoff-Müser Sadatoshi Sakuma Reinhard E Friedrich Robert L Martuza Victor Felix Mautner Andreas Kurtz 《Clinical cancer research》2004,10(17):5677-5683
PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by systemic development of neurofibromas. Early clinical diagnosis can be ambiguous, and genetic diagnosis can be prohibitively difficult. Dysregulation of a number of growth factors has been suggested to be a mechanism of pathogenesis. This study was performed to assess the contribution of circulating growth factors for diffuse tumorigenesis and the diagnostic value of circulating growth factor identification in serum. EXPERIMENTAL DESIGN: The growth stimulation of neurofibroma-derived cells by serum from NF1 patients was tested, and serum growth factor levels in a cohort of NF1 patients (n = 39) between the ages of 7 and 70 years were analyzed. RESULTS: Concentrations of midkine (MK) and stem cell factor, but not epidermal growth factor, were substantially increased in serum of NF1 patients when compared with healthy controls. Within the NF1 group, MK levels increased dramatically at puberty from an average of 0.79 ng/mL in patients <18 years to 1.18 ng/mL in patients >18 years old. Stem cell factor and MK concentrations above a defined threshold in serum of NF1 patients are of diagnostic benefit for 96% of patients in the cohort tested. Furthermore, serum from NF1 patients enhanced proliferation of human neurofibroma-derived primary Schwann cells and endothelial cells substantially better than normal serum. CONCLUSIONS: Enhanced circulating growth factor levels contribute to diffuse tumorigenesis in NF1 and may provide the basis for molecular diagnosis. 相似文献
103.
Martin A. Graham Suresh Senan Hernani Robin Jr. Nils Eckhardt Dennis Lendrem Jeffery Hincks Dennis Greenslade Roy Rampling Stanley B. Kaye Reinhard von Roemeling Paul Workman 《Cancer chemotherapy and pharmacology》1997,40(1):1-10
Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide; SR 259075) is a selective hypoxic cell cytotoxic agent that is bioreductively activated in tumours to a reactive-drug
free radical. Preclinically the agent has been shown to possess additive and synergistic anti-tumour activity in combination
with radiotherapy and chemotherapy regimens. In the present study the pharmacokinetics and metabolism of tirapazamine were
investigated in mice and patients as part of pre-clinical and phase I investigations. The objectives of this work were twofold;
firstly, to evaluate retrospectively the utility of a pharmacokinetically guided dose-escalation (PGDE) strategy for tirapazamine,
and secondly, to investigate if pharmacologically relevant plasma concentrations could be achieved at tolerable doses. Pharmacokinetic
studies for PGDE were conducted in mice at four dose levels ranging from one-tenth of the LD10 to the LD50. The AUC at the LD10 (2932 μg ml-1min) was used to determine a target AUC value of 1173 μg ml-1min (equivalent to 40% of the mouse LD10 AUC) for clinical studies. A phase I study to investigate the tolerance of a single i.v. infusion of tirapazamine (once every
3 weeks) was initiated with close pharmacokinetic monitoring. The starting dose (36 mg/m2) was based on toxicity data obtained in the mouse, rat and dog. Doses were escalated by increases in the volume and duration
of infusion. A retrospective analysis of the pharmacokinetic and toxicity data was then made to determine the utility of a
PGDE approach. The drug exhibited a steep dose-lethality relationship in mice (LD10 294 mg/m2, LD50 303 mg/m2). The major gross toxicities were body-weight loss (15–20%), pilo-erection and hypoactivity at all dose levels. Sporadic
ptosis and conjunctivitis were observed at doses of >300 mg/m2. The plasma elimination of tirapazamine fitted a monoexponential open model, with rapid elimination from the plasma (t
1/2=36±0.65 min) occuring at the LD10 dose of 294 mg/m2. A 10.3-fold increase in dose resulted in a 25.0-fold increase in AUC. Clinically, doses were escalated over the range of
36–450 mg/m2. Ototoxicity (tinnitus and reversible hearing loss) was dose-limiting at 450 mg/m2 and the MTD was 390 mg/m2 for this schedule. Pharmacokinetic analyses in patients revealed that the elimination of tirapazamine in patients was generally
bi-phasic, with low inter-patient variability being found in clearance. A 12.5-fold increase in dose resulted in a 19.0-fold
increase in AUC. There was good quantitative agreement in metabolite formation between mice and humans with respect to the
two- and four-electron bioreductive metabolites. AUC values recorded for tirapazamine at the MTD of 390 mg/m2 (range 1035–1611 μg ml-1min) were similar to the target AUC in mice. Importantly, these levels are consistent with the levels required for radiation-dose
enhancement and effective combination with cisplatin in mice. Given (a) the similarities in plasma pharmacokinetics and metabolism
observed at the target AUC/MTD in mice, rats, dogs and humans, (b) the similar degree of plasma protein binding seen between
species and (c) the relatively low inter-patient variability noted in drug clearance, a successful PGDE approach should have
been feasible. The results also indicate that potentially therapeutic levels of tirapazamine are achievable in patients at
tolerable doses.
Received: 27 May 1996 / Accepted: 30 September 1996 相似文献
104.
U. Eiholzer P. Bodmer M. Bühler U. Döhmann G. Meyer P. Reinhard G. Schimert G. Varga R. Wälli R. Largo L. Molinari 《European journal of pediatrics》1998,157(7):547-552
A longitudinal growth study with monthly measurements during the 1st year of life was conducted by nine paediatricians working
in private practice in Zurich. Of 92 children, none was lost to the study and only 32 of 1104 planned visits were missed;
the quality of the measurements was comparable to that of a specialised university clinic. Compared to the Zurich Longitudinal
Growth Studies, children of this study were considerably heavier and taller. In 92% of the subjects, growth velocity was at
least once outside the reference range (3rd–97th percentile). For weight increments, the corresponding proportion was 87%.
Conclusions The data indicate that current standards for the 1st year of life for the Zurich area might no longer be appropriate and
need to be updated. The currently used velocity percentiles based on 3-monthly measurements are not suitable to assess individual
height and weight increments calculated from monthly measurements.
Received: 9 June 1997 / Accepted in revised form: 21 November 1997 相似文献
105.
The relationship of serum-eosinophil cationic protein and eosinophil count to disease activity in children with bronchial asthma 总被引:1,自引:0,他引:1
106.
Bahram Mohammadi Klaus Krampfl Cener Cetinkaya Heiner Wolfes Reinhard Dengler Johannes Bufler 《Pharmacological research》2005,51(6):587-592
Glycine receptor channels are pentameric ligand-gated ion channels that respond to the application of inhibitory neurotransmitters by opening of a chloride-selective central pore. Topiramate (TPM) is a broad-spectrum antiepileptic drug used as add-on or monotherapy for focal seizures. In the present study the interaction of TPM with glycine receptor channels was studied on outside-out patches from HEK293 cells expressing alpha1beta glycine receptor channels. The patch clamp techniques combined with ultra fast solution exchange enabled us to investigate the kinetics of receptor channels in presence of TPM. Our study showed no agonistic or potentiating effect for TPM on glycine receptor channels. However, in presence of 1 mM glycine + 1 mM TPM, the desensitization got faster and the peak current amplitude decreased. After the end of glycine + TPM pulses, off-currents occurred, suggestive for a specific channel block mechanism. 相似文献
107.
Gerhard Dongowski Bertram Fritzsch Jochen Giessler Albert H?rtl Olaf Kuhlmann Reinhard H H Neubert 《European journal of pharmaceutics and biopharmaceutics》2005,60(1):147-151
The bioavailability of orally administered drugs can be influenced by interactions with food components and by physico-chemical conditions in the upper gastrointestinal tract. Normally, bile salts enhance the transport of lipophilic drugs across mucosal membranes. Bile salts are able to form stable mixed micelles consisting of fatty acids and phospholipids. Conventional micellar systems are known to solubilize lipophilic drugs having a low bioavailability. The influence of bile salts and mixed micelles on the pharmacokinetics of the lipophilic drug quinine was investigated in rabbits. Female rabbits were given intraduadenally quinine (5 mg/kg body weight) without and with incorporation into the micellar or mixed micellar systems. Blood was collected every 30 min for 6 h. In plasma, concentration of quinine was measured using HPLC. The plasma concentration-time profiles of quinine were significantly lower within the first 2 h after administration in presence of both the sodium salt of glycodeoxycholic acid (above the critical micellar concentration) as well as of mixed micellar systems consisting of glycodeoxycholic acid and palmitic acid and/or lecithin. The pharmacokinetic parameters AUC (relative bioavailability) and c(max) of quinine were significantly decreased by micellar systems in rabbits. These mixed micellar systems lower and not as expected, increase the absorption of quinine in vivo. Therefore, quinine should be orally administered at least 1h before food intake, particularly before fat intake. 相似文献
108.
Yahya Mrestani Carmen Mrestani-Klaus Beate Bretschneider Reinhard H H Neubert 《European journal of pharmaceutics and biopharmaceutics》2004,58(3):653-657
Most beta-lactam antibiotics cannot be absorbed orally and, therefore, must be administered intravenously (i.v.) or intramuscularly (i.m.). Because of the obvious drawbacks of drug delivery by injection, the development of alternatives with enhanced oral bioavailability is receiving much attention in pharmaceutical research. Cefuroxime exhibiting significant advantages in the parental treatment of common infections, was used as model drug in the present study. The effect of the cationic absorption enhancers (four quaternary ammonium salts) on the lipophilicity of cefuroxime was investigated by means of the n-octanol/water system. The results on partitioning coefficients in the n-octanol/buffer system were confirmed using an in vitro transport model with artificial (dodecanol collodium membrane) and biological membranes (Charles-River guinea pig). 相似文献
109.
No HeadingPurpose. Industrial products of alkyl polyglycosides (APGs) are widely used as well tolerated surfactants in washing and cleaning agents. APGs belong to the class of nonionic surfactants and are mixtures of molecules consisting of a hydrocarbon chain with Y carbon atoms linked to X sugar residues. Physicochemical properties of APG products strongly depend on the molecular composition. Therefore, a detailed analytical investigation of technical-grade APGs is presented.Methods. Complex mixtures of alkyl/alkenyl polyglycosides (APGs, Plantacare) and mixtures of APGs with other surfactants were analyzed by reversed-phase liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (LC/ESI-QTOF-MS) using methanol-water as mobile phase and gradient elution.Results. Analytes were separated according to the chain length of the alkyl homologs. Under the soft ionization of the ESI technique, mainly [M+Na]+ ions were observed, which proved to be very stable. Additionally [M+H]+ ions were detected. The QTOF mass spectrometer allows to identify even high molecular mass components in the mixtures, and APGs up to eight sugar residues were found. From these data, the alkyl/alkenyl chain lengths and the degree of oligomerization of the sugar moiety for different technical-grade APGs were calculated. Using MS/MS experiments, additional structural and chemical information was obtained.Conclusions. The presented LC/ESI-QTOF-MS approach allows to analyze and characterize various APG products, such as Plantacare. The ability of this LC/ESI-QTOF-MS approach to analyze mixtures of APGs with other surfactants is demonstrated. 相似文献
110.
Progressive multiple sclerosis (PMS) is clinically distinct from relapsing–remitting MS (RRMS). In PMS, clinical disability progression occurs independently of relapse activity. Furthermore, there is increasing evidence that the pathological mechanisms of PMS and RRMS are different. Current therapeutic options for the treatment of PMS remain inadequate, although ocrelizumab, a B-cell-depleting antibody, is now available as the first approved therapeutic option for primary progressive MS. Recent advances in understanding the pathophysiology of PMS provide hope for new innovative therapeutic options: these include antibody therapies with anti-inflammatory, neuroprotective, and/or remyelination-fostering effects. In this review, we summarize the relevant trial data relating to antibody therapy and consider future antibody options for treating PMS.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01214-x. 相似文献